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AACN Clinical Issues Volume 16, Number 3, pp. 277–290 C© 2005, AACN

The Physiology and Processing of Pain A Review

Cynthia L. Renn, RN, PhD, ACNP; Susan G. Dorsey, RN, PhD

Despite the many advances in our understanding of the mechanisms underlying pain processing, pain continues to be a major healthcare problem in the United States. Each day, millions of Americans are affected by both acute and chronic pain conditions, costing in excess of $100 billion for treatment-related costs and lost work productivity. Thus, it is imperative that better treatment strategies be developed. One step toward improving pain management is through increased knowledge of pain physiology. Within the nervous system, there are several pathways that transmit information about pain from the periphery to the brain. There is also a network of pathways that carry modulatory signals from the brain and brainstem that alter the incoming flow of pain information. This article provides a review to the physiology and processing of pain. (KEYWORDS: ascending pain pathways, descending modulation, pain, nociceptors)

Congress declared the years of 2000 to 2010 as the Decade of Pain Control and Research, yet pain continues to be a leading public health and nursing problem in the United States.1 Pain is the principal symptom caus- ing patients to seek medical attention, affect- ing 1 in 5 Americans on any given day.2,3

It is estimated that pain accounts for 1 in

6 visits to a healthcare provider4 and the American Academy of Pain Management reports5 that uncontrolled pain is at epidemic proportions, with 50 million Americans suf- fering from some form of chronic pain and another 25 million experiencing acute pain caused by accident or surgical procedures each year. Studies6–8 estimate that 70 million visits to healthcare providers were motivated by pain and that 4.9 million people visited a healthcare provider for treatment of chronic pain, all at an estimated cost exceeding $100 billion. Further, pain patients and their fami- lies suffer from intangible costs related to the pain, such as decreased quality of life, de- pression, and interpersonal stresses.9

Pain not only affects patients and their families, but also society and the economy as well. Beyond the cost of medical treat- ment, society bears the costs of increased healthcare utilization and lost productivity by patients in pain. More than two thirds of those living with chronic pain have had their pain for 5 or more years, often pro- ducing significant limitations on daily activ- ity, and it is estimated that 36 million Amer- icans missed nearly 4 billion work days due to pain, resulting in a substantial loss of work

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From the Department of Organizational Systems and Adult Health, School of Nursing, University of Maryland, Baltimore, Maryland.

Reprint requests to Cynthia L. Renn, Assistant Profes- sor, University of Maryland School of Nursing, Depart- ment of Organizational Systems and Adult Health, 3rd Floor, 655 West Lombard Street, Baltimore, MD 21201– 1579 ([email protected] ).

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productivity and an estimated cost of $65 bil- lion annually.7

A critical step toward minimizing the phys- ical, emotional, and financial drain on pa- tients and caregivers is improving the clin- ical management of pain. When managing the care of a patient with pain, the advanced practice nurse must work together with the patient to establish a common treatment goal. In many cases, the goal of the treatment strat- egy may be to achieve maximal analgesia (the absence of a pain response to a nox- ious stimulus).10,11 However, when maximal analgesia is not possible, the treatment goal shifts to reducing the pain to a level that the patient finds tolerable and allows for the per- formance of normal activities of daily living. Upon establishment of the treatment goal, the next step is to develop a plan to meet that goal. A key factor that aids in the process of selecting the most appropriate treatment modalities, in addition to a thorough pain assessment, is an in-depth understanding of pain physiology. A thorough understanding of how pain is processed at each stage in the peripheral and the central nervous sys- tems allows the treatment strategy to be tai- lored to meet the needs of the individual patient. This article provides a primer on ma- jor structures and processes involved in pain physiology.

� What Is Pain?

When a region of the body is exposed to a tissue-damaging or potentially tissue- damaging insult, one experiences the un- pleasant sensation of pain.12 Pain has been described as a multifaceted and highly sub- jective experience that is unique to each person. Pain is not only influenced by phys- iological processes, but also influenced by psychological and emotional processes as well. It has been reported that the inten- sity of pain can be influenced by contex- tual cues. For example, similar types of trau- matic injury may be seemingly painless in certain situations and extremely painful in others.13,14 This phenomenon was first de- scribed by Beecher,13 who found that soldiers with severe wounds often reported little pain while civilians with similar injuries typically reported severe pain. The subjective nature

of the pain experience led McCafferey15 to define pain as “whatever the experiencing person says it is, existing whenever the ex- periencing person says it does.”(p7) Pain has further been defined by the International As- sociation for the Study of Pain (IASP)10 as “an unpleasant sensory and emotional expe- rience associated with actual or potential tis- sue damage or described in terms of such damage.”(p250)

Two broad categories of pain, acute and chronic, are seen in the clinical setting. Un- der these broad categories fall the subtypes of pain, which include inflammatory, neuro- pathic, cancer, etc. Acute pain tends to be of a short duration, typically has an identifiable cause, and is focal to the site of injury.10–13,16

Further, acute pain functions as an endoge- nous protective mechanism that signals the brain of the occurrence of real or poten- tial tissue injury, thus prompting a protective response.12 Clinically, acute pain functions as a symptom, tends to be self-limited, and gen- erally responds to a straightforward treatment plan with a good to excellent prognosis.16

However, pain can persist beyond the point of tissue healing and develop into a chronic and debilitating state. Chronic pain is unre- lenting, has no identifiable cause, spreads be- yond the original site of injury, and serves no biological function.10–13,16 Clinically, chronic pain has the characteristics of a disease state, can produce psychological disturbances, re- quires complex treatment strategies, and typ- ically has a poor prognosis.16

� Pain Transmission: The Ascending Pain Pathways

The ascending pain pathways transmit noci- ceptive information from peripheral tissues to the cerebral cortex for interpretation as pain. The ascending pathways are complex struc- tures, involving both the peripheral (PNS) and central nervous systems (CNS).

Nociception

Nociception, the initial processing of pain, involves a system of mechanisms that en- code and transmit the pain signal, along the ascending pathway, from the point of nox- ious stimulation in the periphery to higher

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Figure 1. Ascending pain pathway. The ascending pain pathway transmits nociceptive information from peripheral tissues (1) via a primary afferent nerve fiber, which enters the spinal cord in the dorsal horn (2) where it synapses with a second-order neuron. The second-order neuron travels up through the spinal cord (3) and brainstem, synapsing in the tha- lamus with a third-order neuron that transmits the nociceptive information to the brain (4) for interpretation as pain. Adapted with permission from Fields and Basbaum.63(p310)

centers in the CNS, including the cerebral cortex where an awareness of the presence of pain occurs12 (see Figure 1). The first step in the complex pain process is the transduction of a noxious stimulus (nocicep- tion) by specialized nerves (nociceptors).17,18

Nociceptors are found in most organs and tissues in the body and are activated by ei- ther a noxious mechanical (touch or pres- sure), thermal (hot or cold), or chemical (en- dogenous or exogenous) stimulus12,17,18 (see Figure 2). The term noxious is applied to nociceptive stimuli because nociceptors are activated in response to strong stim- uli that fall in the tissue-damaging range, whereas nonnociceptive mechanoreceptors, thermoreceptors, and chemoreceptors re- spond to milder stimuli that fall in a range below the tissue-damaging level.12,17,18 In ad- dition to exogenous chemicals that stimulate

nociceptors, a number of endogenous chemi- cals have been identified that can activate no- ciceptors, including potassium, bradykinin, serotonin, histamine, prostaglandins, and others.19–23

Spinal Dorsal Horn

When a noxious stimulus is transduced by a nociceptor, a signal is generated that is trans- mitted as an electrical action potential along small diameter A-delta (myelinated, fast transmission, sharp or pricking first pain)24,25

and C (unmyelinated, slow transmission, dull or burning second pain)25,26 primary affer- ent nerve fibers to the gray matter of the spinal cord (see Figure 2 inset). On cross- section, the spinal gray matter forms a but- terfly shape and can be divided into 10 lami- nae, or layers, which are numbered I through

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Figure 2. Pain transmission from peripheral tissues to the spinal cord. Noxious stimuli (thermal, chemical, or mechanical) that are applied to peripheral tissues activate nociceptors that are located within the tissues. The stimulus is transduced by the nociceptor to generate a nociceptive signal that is transmitted as an action potential along a primary afferent nerve to the dorsal horn of the spinal cord. Within the primary afferent nerve (inset), the signal can be transmitted rapidly by myelinated A-delta fibers or more slowly by unmyelinated C fibers. The dorsal root ganglion is part of the primary afferent nerve, located near the spinal cord, and contains the cell bodies of all fibers traveling within the nerve.

IX, from dorsal to ventral, with X surround- ing the central canal18,27,28 (see Figure 3). Pain processing occurs predominantly in laminae I, II, and V.18,28

The primary afferent fibers enter the spinal cord in the dorsolateral aspect of the gray matter (the dorsal horn) through the dorsal root. Upon entering the dorsal horn, the pri- mary afferents bifurcate in a “T” pattern and travel 2 to 3 spinal segments within Lissauer’s

Figure 3. Structure of the spinal cord. The gray matter is a butterfly-shaped area in the center of the spinal cord. The gray matter contains unmyelinated nerve fibers and the cell bodies of the neurons. The spinal gray matter is surrounded by white matter, which is composed of myelinated nerve fibers. The central canal is a conduit for cerebral spinal fluid and runs the full length of the spinal cord. The spinal gray matter has two dorsal and two ventral horns. The dorsal horns, comprising the dorsal aspect of the gray matter bilaterally, are primarily responsible for receiving and transmitting sensory information. The ventral horns, comprising the ventral aspect of the gray matter bilaterally, are primarily responsible for sending motor information out to the periphery. Based on cellular organization, the gray matter can be divided into ten laminae (layers), which are numbered I-IX from dorsal to ventral. Lamina X surrounds the central canal.

tract in both the rostral (toward the nose) and caudal (toward the tail) directions. As the pri- mary afferents travel in Lissauer’s tract, they send collateral projections to the gray matter along the entire 4 to 6 segment length,12,29,30

thus transmitting the pain signal over a broad area of the spinal cord rather than to a dis- crete location (see Figure 4). This is impor- tant in the case of spinal pathology, such as a lesion, which could block the signal if it is

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Figure 4. Lissauer’s tract and primary afferent collat- eralization in the spinal cord. The primary afferent fiber (PAF) enters the spinal dorsal horn and the nerve fibers bifurcate in Lissauer’s tract. After bifurcation, the nerve fibers travel 2–3 spinal segments in both the rostral and caudal directions. Throughout the length of travel in Lis- sauer’s tract, the afferent nerve fibers send out collat- eral projections into the dorsal horn to transmit the pain signal across multiple segments of the spinal cord.

transmitted to a discrete location within the area of pathology.

In the dorsal horn, the primary afferent fibers synapse (connect), either directly or in- directly (via interneurons), with second-order projection neurons and convey the nocicep- tive message through the release of a vari- ety of neurotransmitters, such as the exci- tatory amino acid glutamate or the peptide substance P12,31,32,33 (see Figure 5). After the nociceptive signal has been received in the dorsal horn, the information is transmitted to higher centers in the CNS by projection neurons.17,18,34,35

Ascending Tracts

The projection neurons transmit the noci- ceptive signal rostrally along the ascend- ing pathways in the spinal cord to vari- ous supraspinal structures in the brainstem and diencephalon, including the medullary reticular formation, periaqueductal gray, parabrachial region, hypothalamus, thala- mus, and various limbic structures.17,18,34,35

The function of the ascending pathways is simply the transmission of the nociceptive information. Within the supraspinal target structures of the ascending pathways, third-

order neurons further process the nocicep- tive signal and transmit it to cortical and lim- bic structures, where the signal is interpreted as pain.12

The organization of and the neuroanatomy within the ascending pain pathways are quite complex.17,18,34,35 The most prominent and well-described of the ascending pathways is the spinothalamic tract (STT—spinal cord to thalamus), which is thought to trans- mit sensations of pain, temperature, and touch.12,17,18 The majority of the projection neurons that travel in the STT originate in the superficial laminae I and II and deeper lamina V of the spinal dorsal horn.36,37 Be- fore ascending, the STT neurons decussate (cross midline) through the ventral white commissure (junction between two parts) to the opposite ventrolateral quadrant of the spinal cord white matter, where they ascend in the ventrolateral funiculus (VLF—bundle of nerve fibers) to the thalamus12,36,37 (see Figure 6a). A second prominent ascending pathway that is involved in pain transmis- sion is the spinomesencephalic tract (SMT— spinal cord to mesencephalon), which origi- nates in laminae I, II, and V of the spinal dor- sal horn, decussates, and also travels in the VLF to the mesencephalon (also known as the midbrain)12,36,38,39 (see Figure 6b). Within the midbrain, the neurons in the SMT termi- nate in several areas, such as the periaque- ductal gray (PAG) and nucleus cuneiformis, among others.18,39–41 A third tract that has also been shown to convey nociceptive in- formation is the spinoreticular tract (SRT— spinal cord to reticular formation), which terminates in the reticular formation of the medulla12,17,18 (see Figure 6c). Though each ascending tract has a primary target structure, they also send collateral projections to other areas of the brainstem as they pass through. When the projections from the spinal cord reach their targets, they synapse with third- order neurons that serve as relays and project to other regions within the brainstem, dien- cephalons, and forebrain.12,17 While the three pathways described above are thought to be the predominant pathways involved in pain transmission, they do not constitute a complete list of all ascending sensory path- ways. A detailed description of the remain- ing pathways is beyond the scope of this review.

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Figure 5. Synapse of the primary afferent fiber with a projection neuron in the dorsal horn. The primary afferent fiber (PAF) enters the spinal dorsal horn and synapses (A) directly with a projection neuron (PN; second-order neuron) or (B) with an interneuron (IN) that then synapses with a projection neuron. The pain signal is transmitted across the synapse by the release of neurotransmitters from the presynaptic neuron that cross the synaptic cleft and bind with receptors on the postsynaptic neuron.

Thalamus The thalamus is thought of as the major supraspinal relay structure for the integration

Figure 6. Ascending transmission tracts. (A) Spinothalamic tract (STT). The projection neurons that form the STT originate predominantly in laminae I, II, and V of the spinal dorsal horn. The STT neurons decussate (cross midline) through the ventral white commissure to the opposite ventrolateral quadrant of the spinal cord. In the ventrolateral quadrant, the STT neurons ascend from the spinal cord to the thalamus in the ventrolateral funiculus (VLF; bundle of fibers). (B) Spinomesencephalic tract (SMT). The neurons that form the SMT also originate predominantly in laminae I, II, and V of the dorsal horn. The SMT neurons decussate through the ventral white commissure to the VLF, where they ascend from the spinal cord to the mesencephalon and terminate in several structures such as the periaqueductal gray (PAG). (C) Spinoreticular tract (SRT). The SRT neurons originate predominantly in laminae I, II, and V of the dorsal horn, decussate through the ventral white commissure to the VLF and ascend from the spinal cord to the reticular formation of the medulla. Adapted with permission from Fields and Basbaum.63(p310)

and transfer of ascending nociceptive infor- mation to the cerebral cortex.18,42 As such, the thalamus not only receives input from the

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STT, but it also receives input from collateral projections sent out of the other ascending tracts that carry nociceptive information.18,42

Within the thalamus, nociceptive informa- tion regarding the type, temporal pattern in- tensity, and topographic localization of the pain is encoded prior to sending the informa- tion onward to limbic structures and cortical sites.12,18,42

Cerebral Cortex

Ultimately, the nociceptive signal reaches the cerebral cortex where it is integrated and un- dergoes cognitive and emotional interpreta- tion as stemming from a painful stimulus.12,43

The nociceptive signal is transmitted from the thalamus to a variety of cortical sites: the somatosensory S1 area and S2 area, the insular cortex, the anterior cingulate cortex, and the medial prefrontal cortex.44–48 Within these cortical regions, there is a complex network of interconnections that include the thalamus and limbic structures.49 This net- work of cortical structures is responsible for the sensory-discriminative (perception of the intensity, location, duration, temporal pat- tern, and quality of noxious stimuli) and motivational-affective (relationship between pain and mood, attention, coping, tolerance, and rationalization) components of the pain experience.12,50,51

� Descending Modulation of Nociception

The idea that pain undergoes modulatory ef- fects from higher areas of the CNS was first introduced by Head and Holmes.52 Over the past century, a large volume of information has been learned regarding pain perception and modulation. Thus, much effort has been put into understanding the mechanisms in- volved in the modulatory process.53–55

Several decades after Head and Holmes52

first theorized that pain is under the influ- ence of higher areas in the CNS, studies con- firmed their theory by providing evidence that a number of supraspinal sites contribute to the control of ascending sensory input by exerting tonic inhibitory control of neu- rons in the spinal dorsal horn.56–58 Further

research into the contribution of supraspinal structures to nociceptive modulation showed that the mammalian CNS has several well- defined, supraspinally organized descending pathways. These pathways form a network of neural systems that modulate the ascending transmission of nociceptive information, with the most well-described being the circuitry mediating the brainstem control of nocicep- tive transmission at the level of the spinal dor- sal horn.53–63

The effects of descending modulation are exerted in the spinal dorsal horn on the synapse between the primary afferent and projection neurons or on interneurons that synapse with projection neurons (see Figure 7). This synapse in the dorsal horn is the point where nociceptive information is first integrated before being transmitted to higher centers in the CNS.12,18,54,64 The descending modulatory effect is applied ei- ther by inhibiting the release of neurotrans- mitter from the primary afferent fiber (see Figure 7A) or by inhibiting the function of neurotransmitter receptors on the post- synaptic neuron (see Figure 7B). Several supraspinal sites are known to contribute to the descending modulation of noci- ception, either directly (sending projection neurons to the spinal cord) or indirectly (sending projection neurons to other re- gions in the brainstem that send projec- tions to the spinal cord). These include the PAG, locus coeruleus (LC), and the rostral ventromedial medulla (RVM) among others.12,54,63,65,66

Periaqueductal Gray

The PAG is a midline structure, composed of densely packed heterogeneous neurons, that surrounds the cerebral aqueduct through- out the mesencephalon67,68 (see Figure 8). It has been well established that the PAG is a major component of the pain modula- tory circuitry, since Reynolds53 first reported the phenomenon of stimulation produced analgesia after performing abdominal surgery on an unanesthetized rat while electrically stimulating the PAG.59,69 Given that few PAG efferents project directly to the spinal dor- sal horn,70–72 researchers have focused on discovering other pathways that mediate the

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Figure 7. Effect exerted by a descending modulatory projection neuron on the synapse between a primary afferent fiber and a projection neuron in the dorsal horn. The descending modulatory projection neuron can exert its effect by inhibiting the release of neurotransmitters from the primary afferent fiber (PAF) in the spinal dorsal horn (A) or by inhibiting neurotransmitter receptors on the ascending projection neuron (PN; B), thus altering the flow of nociceptive information to the brain.

spinal effects of PAG stimulation. It was found that the modulatory effect of the PAG is exerted indirectly through efferent connec- tions with a variety of brainstem structures, such as the RVM, parabrachial nucleus, locus coeruleus, and the A5 and A7 noradrenergic cell groups.73–78

LOCUS COERULEUS: The LC is a bilateral struc- ture, composed of noradrenergic neurons, that is located in the pons on the border of the fourth cerebral ventricle79 (see Figure 9). Bilateral projections from the LC and nearby A7 cell group descend primarily to the con-

Figure 8. The periaqueductal gray (PAG). The PAG is a midline structure that surrounds the cerebral aque- duct in the mesencephalon of the brainstem.

tralateral spinal dorsal horn laminae I, II, and V where they exert an antinociceptive effect.79–81 In addition to the intrinsic antinoci- ceptive effects of the pontine noradrener- gic cell groups, they also receive neuronal projections from the RVM and PAG, thus serving as relays for the modulatory effects from the RVM and PAG to the spinal dorsal horn.82,83

Rostral Ventromedial Medulla

The RVM has been studied at length and is recognized as a major component of the

Figure 9. The locus coeruleus (LC). The LC is a bi- lateral structure that is adjacent to the fourth ventricle in the pons of the brainstem.

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Figure 10. The rostral ven- tromedial medulla (RVM). The RVM is a region of the ventral medulla that includes the midline nucleus raphe magnus (NRM), gigantocellularis pars alpha (GiA) and lateral paragigantocellularis (LPGi).

pain modulatory circuitry, exerting its own modulatory effects in addition to relaying the modulatory effects from higher brainstem sites.54,84,85 It is a large region of the medulla that includes the midline nucleus raphe mag- nus (NRM) and portions of the adjacent retic- ular formation; the nucleus reticularis gigan- tocellularis pars alpha (GiA) and the nucleus paragigantocellularis lateralis (LPGi) (Figure 10). Efferent projections from the RVM ex- tend bilaterally, have been identified in all levels of the spinal cord, and comprise a major portion of the neurons projecting to the spinal dorsal horn.61,62,86–90 These neurons have widely collateralized yet lamina-specific projections,91 with dense bilateral termina- tions in laminae I, II, and V of the spinal cord dorsal horn.63,92,93 While all of the com- ponents of the descending modulatory net- work are important, the PAG and RVM have been shown to play key roles in the under- lying mechanisms of pain modulation.54,63,85

Further, the PAG to RVM projection is criti- cal for the PAG to exert its descending mod- ulatory effect on dorsal horn nociceptive neurons.76,84,93,94

The RVM exerts its modulatory effect on nociceptive transmission at the spinal level, producing antinociception to painful stimuli.73,74,95 During persistent noxious stim- ulation, such as during a prolonged inflam- matory state, there is continued activation of the descending pain modulatory circuitry and increased neuronal activity in the RVM that results in a progressive enhancement of de- scending modulation of spinal nociceptive transmission.96–102

Biphasic Modulation

The descending modulation of nociception is not wholly inhibitory. Several lines of ev-

idence demonstrate time-dependent bipha- sic properties of the pain modulatory system that can both inhibit and facilitate nocicep- tive transmission.97,100,103–108 However, many aspects of the underlying mechanisms of no- ciceptive modulation and the shift from facil- itation to inhibition remain unclear.

The RVM is one area in the pain mod- ulatory system that puts forth opposing modulatory effects and is a crucial site for balancing descending modulation. When activating the descending pathways that orig- inate in the RVM, the resulting effect (in- hibitory or facilitatory) is dependent on the intensity and nature of the intra-RVM stimulus.106–108 Although the circuitry respon- sible for generating facilitatory and inhibitory modulation may be distinct, an anatom- ical and neurochemical differentiation of the bimodal modulatory structures has not been determined.97,103,104,106,109 However, sev- eral studies that used either electrical stimula- tion or lesions have shown opposing modu- latory effects from the different subregions of the RVM.107,109,110 The effects of both descend- ing inhibition and facilitation have been ob- served during multineuron recording in the dorsal horn, where it has been shown that neighboring neurons are simultaneously un- der facilitatory and inhibitory control from supraspinal structures.111 The balance be- tween inhibition and facilitation determines the net effect of descending modulation on nociceptive transmission.18,34,110,112

In summary, the processing of pain is a complex phenomenon, involving both the peripheral and central nervous systems. No- ciceptive information regarding actual or po- tential tissue injury is transmitted from pe- ripheral nerve endings (nociceptors), via a complex series of ascending pathways, to the brain. Within the brain, the nociceptive

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signals are further processed in the so- matosensory cortex and interpreted as pain. As the ascending nociceptive information passes through the brainstem and reaches the brain, it triggers the activation of a net- work of brainstem structures and pathways that exert a modulatory effect on nociceptive transmission. The structures involved in pain modulation send neuron projections from the brainstem to the spinal dorsal horn where their modulatory effect alters the transfer of nociceptive information from the primary af- ferent to the second-order neuron. Thus, the flow of further nociceptive information from the periphery is either inhibited (resulting in less pain) or facilitated (resulting in more pain).

� Clinical Significance

New scientific discoveries that stem from re- search into the mechanisms that underlie pain can lead to the development of new treatment strategies for managing patients with pain, whether acute or chronic. For ex- ample, it is known that nonsteroidal anti- inflammatory drugs (NSAIDs) block the syn- thesis of prostaglandins, which play a role in the sensitization of nociceptors, thus de- creasing pain from inflammation. However, prostaglandins do not act alone. There are many other endogenous substances (inflam- matory mediators) that can sensitize noci- ceptors, such as bradykinin, serotonin, cy- tokines, and others. Therefore, pain research can lead to the development of new pharma- cological agents that are directed against the actions of these sensitizing substances and provide new avenues of pain management.113

Our understanding of the mechanisms un- derlying pain and endogenous modulation is increasing, and many targets exist along the pain pathways for intervention in the treat- ment of pain. Pain transmission can be inter- rupted in the periphery by giving drugs that block sensitization of nociceptors (NSAIDs) or by blocking nerve transmission (lidocaine injection into a peripheral nerve). Pain per- ception can also be altered by giving drugs that work in the CNS (opioids). By gaining in- creased knowledge of the how the pain pro- cessing system works, the advanced practice nurse will be better able to design a treatment

plan that is appropriate for each individual patient.

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